The etiology of amyotrophic lateral sclerosis (ALS), a degenerative disorder characterized by selective death of motor neurons, is unknown. Prior studies by the PI have demonstrated large increases in mercury in ALS tissues compared to controls, supporting the hypothesis that toxic metals may be pathogenetic in ALS. However the hypothesis remains quite speculative because the cellular distribution of toxic metals has not been investigated to determine if mercury is, in fact, selectively enriched in motor neurons. In the proposed study, Laser Activated Microprobe Mass Analysis (LAMMA) will be used to measure the abundances of mercury and other elements in motor neurons. LAMMA is a new technique, capable of probing specific regions of individual cells and determining the complete elemental composition with a spatial resolution of 1-2 microns. The brain and spinal cord of ALS and age-matched controls will be obtained; regions known to be pathologically involved in ALS (motor cortex, ventral spinal cord) will be analyzed using LAMMA. In controls, mercury abundance will be assayed in the nucleus and cytoplasm of motor neurons and compared to other cells to test the hypothesis that mercury is selectively accumulated by motor neurons. In ALS, particular attention will be directed to motor neurons in various stages of degeneration including analysis of proximal axonal spheroids to determine if neuronal mercury accumulation preceeds, or is a consequence of, neuronal death. Mercury will be assayed in the Onufrowicz nucleus (motor neurons innervating the bladder; spared in ALS) to determine if these cells differ from susceptible motor neurons in the cord with regard to their burden of toxic metals. Comparisons will be made between ALS and controls on a region-by-region and cell type-by-cell type basis to establish if the relative abundance of mercury is increased in ALS. Bulk tissue samples from the same patients will be analyzed using neutron activation to relate the LAMMA data directly to previous studies by the PI and others. Although the primary focus of work is mercury, both LAMMA and neutron activation provide simultaneous analysis of multiple elements postulated by others to be involved in the pathogenesis of ALS (eg: lead, aluminum, selenium). The results of this study will provide the first measurement of mercury abundances in motor neurons of sporadic cases of ALS. These analyses will provide a direct test of the hypothesis that mercury accumulation in spinal motor neurons marks the cell as susceptible for ALS-type degeneration to occur.